Mechanism of increase genomic instability in aging yeast

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DESCRIPTION (provided by applicant): Age is the greatest carcinogen, yet the mechanism by which the incidence of cancer dramatically increases as humans age is unclear. In an effort to better understand this phenomenon, we have sought to develop a system in the yeast, Saccharomyces cerevisiae that shows one of the hallmarks of cancer - genomic instability - as a function of cellular age. Specifically, we examined the relationship between aging and genomic instability by monitoring loss of heterozygosity (LOH) on two different chromosomes during replicative aging in yeast. We discovered that aging yeast mother cells underwent a switch to a nearly 100-fold increase in LOH in their progeny. After the switch, the increased rate of LOH remained constant throughout the remainder of the lifespan. Extending lifespan did not alter the onset nor frequency of age-induced LOH, suggesting that the aging "clock" that sets off hyper-LOH is distinct from that which regulated replicative lifespan. Furthermore, age-induced LOH is qualitatively distinct; in young cells LOH proceeds primarily by reciprocal recombination, whereas in old cells it is non-reciprocal and proceeds by break-induced replication with a striking daughter cell bias. We now propose to use the powerful collection of resources and tools available in S. cerevisiae to develop our understanding about age-induced LOH. We anticipate that genes and processes identified in this analysis will lead us to a molecular understanding of how genomic instability increases in aging yeast cells. These may then serve as means to identify genes and processes in human cells that become defective with age and ultimately lead to aging-dependent diseases such as cancer.